This NATIONAL COOPERATIVE DRUG DISCOVERY GROUP (NCDDG) competitive renewal grant application seeks to continue to develop a new form of anticancer therapy utilizing monoclonal antibodies (MAbs) that inhibit the activation and function of receptors for growth factors. The participants include laboratory scientists and clinical investigators from Memorial Sloan- Kettering Cancer Center, the Salk Institute, the Scripps Research Institute, the University of Arizona and the University of Iowa. There have been close and productive collaborations between the three original program leaders of this NCDDG for over ten years. In collaboration with the NCI, each of the research programs has produced antireceptor MAbs, evaluated them in cell culture and xenograft models, and performed Phase I clinical trials with them. Our approach to new drug development remains current and highly relevant: there is no doubt that interruption of receptor mediated growth signals and signalling pathways is an approach that will produce new anticancer therapies. Mendelsohn will pursue our finding that combination therapy with anti-EGF receptor MAb plus a chemotherapeutic agent (doxorubicin, cisplatinum, or Taxol) can cause eradication of well-established human tumor xenografts, and will explore other combination therapies. Reisfeld will investigate the capacity of engineered fusion proteins of antireceptor MAb plus cytokine to target immune effector cells and mediate destruction of tumor vasculature at the site of malignancy in murine and xenograft models. Taetle and Kemp will continue to explore antitransferrin receptor MAbs, alone and in combination with other agents, as anticancer therapy, and will pursue new antireceptor antibodies which potentiate programmed cell death (apoptosis). Trowbridge will explore the trafficking of antitransferrin receptor MAbs across the blood-brain barrier, as a model for a novel delivery mechanism for immunoconjugated anticancer agents. Each Program is targeted to drug discovery which will lead to future clinical trials designed by this group of collaborating investigators.